FDA identifies biomarker for immune response to FVIII products used to treat hemophilia A

Scientists at the U.S. Food and Drug Administration (FDA) developed a technique that enables them to determine whether immune system cells called dendritic cells appear primed to trigger the production of antibodies against Factor VIII (FVIII) products used to treat hemophilia A. These primed cells present specific FVIII-derived peptides on the surface. The technique might enable scientists to use the presence of such primed dendritic cells as biomarkers for potential immune reactions that would block the therapeutic effects of FVIII.

Patients with hemophilia lack FVIII, a protein that is part of the cascade of chemical reactions required to form blood clots and stop bleeding. The disease causes prolonged bleeding from wounds, bleeding into muscles and joints, and spontaneous bleeding inside the body. Treatment consists of replacing FVIII using either rFVIII or pdFVIII.

The biomarker is important because the production of antibodies against protein drugs is a major safety and efficacy concern during both drug development and the agency’s subsequent regulation of such products.Strategies that identify individuals and groups of individuals at risk for producing antibodies against such drugs would mitigate this problem.

The new technique also enabled the FDA scientists to explain previous clinical studies showing that FVIII derived from human blood plasma (plasma-derived FVIII, pdFVIII) may trigger a significantly less immune response than if it is made through genetic engineering (recombinant FVIII, rFVIII).

Dendritic cells capture and digest foreign molecules and display pieces of them on their outside membrane as an initial step in the immune response that produces antibodies against these molecules. The FDA technique enables researchers to determine whether dendritic cells display more FVIII fragments if they are exposed to one type of FVIII in contrast to other types of this protein. Using the technique, the FDA scientists found that some FVIII products cause dendritic cells to display more fragments of the protein than other types of FVIII. Therefore, this biomarker could potentially help to identify whether a specific FVIII product is likely to trigger dendritic cells to initiate the immune system to produce antibodies against FVIII products.

Although previous research suggested that rFVIII might be more likely than pdFVIII to trigger an immune response through the activation of dendritic cells, until now, researchers had not been able to explain why this occurred.

It was already known that dendritic cells absorb and dismantle foreign molecules that enter the body, including drugs like rFVIII and pdFVIII. These cells then use molecules on their surface called the major histocompatibility complex (MHC) to display the pieces of the proteins, called peptides, to another part of the immune system called T cells. T cells subsequently trigger an antibody response to the full protein drug that inhibits its therapeutic effect.

In laboratory studies, however, adding peptide fractions of the drug to cultures of dendritic cells to see which ones bound to MHC molecules could not answer the question of whether dendritic cells naturally produce those peptides themselves when breaking down the drug. In addition, providing the dendritic cells with the full drug to process naturally did not answer the question of which peptides on the MHC molecules stimulate T cells.

Therefore, the FDA scientists used a technique called the mass spectrometry-based major histocompatibility complex (MHC)–associated peptide proteomics (MAPPs) assay to determine which peptide fragments of rFVIII and pdVIII made by the dendritic cells were bound to their MHC molecules.

The scientists were able to prove that dendritic cells from hemophilia A patients as well as healthy individuals display fewer peptides that stimulate T cells when they received pdFVIII than when they were administered rFVIII.

The results suggest that pdFVIII made by extracting the protein from blood plasma could yield a product that is less likely to trigger production of peptide fragments by dendritic cells than does rFVIII. In turn, this would reduce the likelihood that treatment with pdFVIII, compared to rFVIII, would result in the immune system produce antibodies that inhibit the therapeutic effect of the drug.